GTP-cyclohydrolase I gene mutations in patients with autosomal dominant and recessive GTP-CH1 deficiency: identification and functional characterization of four novel mutations.

TitleGTP-cyclohydrolase I gene mutations in patients with autosomal dominant and recessive GTP-CH1 deficiency: identification and functional characterization of four novel mutations.
Publication TypeJournal Article
Year of Publication2004
AuthorsGaravaglia, B, Invernizzi, F, Carbone, MLAgostoni, Viscardi, V, Saracino, F, Ghezzi, D, Zeviani, M, Zorzi, G, Nardocci, N
JournalJ Inherit Metab Dis
Volume27
Issue4
Pagination455-63
Date Published2004
ISSN0141-8955
KeywordsAdult, Female, Frameshift Mutation, GTP Cyclohydrolase, Humans, Male, Mutagenesis, Site-Directed, Mutation, Mutation, Missense, Polymerase Chain Reaction, Saccharomyces cerevisiae
Abstract

GTP-cyclohydrolase I (GTP-CH1, EC 3.5.4.16) is encoded by the GCH1 gene. Mutations in the GCH1 gene cause both dopa-responsive dystonia (McKusick 128230) and recessive GTP-CH1 deficiency (McKusick 600225). The exact molecular mechanism resulting in decreased GTP-CH1 activity in the patients is still obscure. We report the clinical features and molecular and functional study of the GCH1 gene in eight Italian patients affected by dominant and recessive GTP-CH1 deficiency. All the studied patients had mutations in the GCH1 gene. Three missense mutations (V205G, K224R, P199A), a frameshift mutation (Delta G693), and a splice-site mutation (ivs5 + 1g > c) were found. Except for K224R these are all novel mutations. To analyse the defect caused by the novel mutations, an in vivo functional assay in a Saccharomyces cerevisiae strain lacking the endogenous gene encoding GTP-CH1 ( FOL2 ) was performed. Complementation analysis showed that the Delta G693 and V205G mutations abolish the enzymatic function, while the P199A mutation causes a conditional defect. In conclusion, the clinical phenotypes displayed by our patients confirm the wide clinical spectrum of the disease and further support the lack of correlation between a given mutation and a clinical phenotype. Complementation analysis in yeast is a useful tool for confirming the pathogenetic effect of GCH1 mutations.

DOI10.1023/B:BOLI.0000037349.08483.96
Alternate JournalJ. Inherit. Metab. Dis.
Citation Key10.1023/B:BOLI.0000037349.08483.96
PubMed ID15303002
Grant ListE.0713 / / Telethon / Italy